The Luminal Progenitor Compartment of the Normal Human Mammary Gland Constitutes a Unique Site of Telomere Dysfunction

Kannan, Nagarajan; Huda, Nazmul; Tu, LiRen; Droumeva, Radina; Aubert, Geraldine; Chavez, Elizabeth A.; Brinkman, Ryan R.; Lansdorp, Peter M.; Emerman, Joanne T.; Abe, Satoshi; Eaves, Connie J.; Gilley, David

doi:10.1016/j.stemcr.2013.04.003

Cited by 53 publications

(63 citation statements)

References 42 publications

(58 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The glutathione-independence of the LPs and their more differentiated LC progeny is associated with up-regulated expression of numerous enzymes that, in combination, appear able to counteract at least some of the potentially lethally mutagenic effects of the ROS levels that these cells produce. These observations add to a growing body of data revealing other mechanisms that predispose normal human luminal cells to DNA damage (28). Thus, the up-regulated expression of multiple antioxidant enzymes at the point of mammary progenitor cell restriction to the luminal lineage could contribute to multiple mechanisms that promote the death of LCs and allow lumen formation (5).…”

Section: Discussionmentioning

confidence: 82%

Glutathione-dependent and -independent oxidative stress-control mechanisms distinguish normal human mammary epithelial cell subsets

Kannan

Nguyen

Makarem

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Mechanisms that control the levels and activities of reactive oxygen species (ROS) in normal human mammary cells are poorly understood. We show that purified normal human basal mammary epithelial cells maintain low levels of ROS primarily by a glutathione-dependent but inefficient antioxidant mechanism that uses mitochondrial glutathione peroxidase 2. In contrast, the matching purified luminal progenitor cells contain higher levels of ROS, multiple glutathione-independent antioxidants and oxidative nucleotide damage-controlling proteins and consume O 2 at a higher rate. The luminal progenitor cells are more resistant to glutathione depletion than the basal cells, including those with in vivo and in vitro proliferation and differentiation activity. The luminal progenitors also are more resistant to H 2 O 2 or ionizing radiation. Importantly, even freshly isolated "steady-state" normal luminal progenitors show elevated levels of unrepaired oxidative DNA damage. Distinct ROS control mechanisms operating in different subsets of normal human mammary cells could have differentiation state-specific functions and long-term consequences.human epithelial stem and progenitor cells | mammary differentiation | 3D clonogenic assay | superoxide dismutase | peroxiredoxin C ellular synthesis of different reactive oxygen species (ROS) results primarily from the incomplete reduction of molecular oxygen in mitochondria to generate free radical superoxide anions. ROS also are produced when cells are exposed to different environmental sources of oxidative stressors, including ionizing radiation. Together, these regulate many normal cellular processes and also contribute to DNA damage, tumorigenesis, and cell death (1-3).In mice, the inner layer of "luminal" epithelial cells of the normal adult mammary gland have been found to contain higher levels of ROS than the outer "basal" layer of epithelial cells (4). The basis for these differences in ROS levels in the two cell types has been attributed to differences in their content of mitochondria; however, their stress response mechanisms have not been defined. Even less is known about ROS levels and their control in the normal adult human mammary gland, which consists of a similar continuous bilayered epithelial network of ducts and terminal alveolae. MCF10A cells are an immortal but nontumorigenic human mammary cell line that, when grown in 3D Matrigel cultures, generates multilayered spheres in which a lumen forms owing to the acquisition of lethal levels of ROS by the inner cells (5). These studies have suggested that ROS regulation plays an important role in the structural morphogenesis and homeostasis of normal adult human mammary tissue.Here we report the results of experiments designed to investigate the levels of ROS and their control in highly purified populations of viable luminal progenitors (LPs) and basal cells (BCs) isolated from normal human breast tissue (6-8). Our results confirm the different levels of ROS identified in the corresponding subsets of mouse mammary cells an...

show abstract

Section: Discussionmentioning

confidence: 82%

Glutathione-dependent and -independent oxidative stress-control mechanisms distinguish normal human mammary epithelial cell subsets

Kannan

Nguyen

Makarem

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The highest levels of AR mRNA in the mammary epithelium of mice and humans have been found within the HS-MEC-enriched population isolated by fluorescenceactivated cell sorting (FACS; Lim et al 2010, Kannan et al 2013; Table 1). Another mouse study reported a higher level of Ar mRNA within the FACS-sorted basal MEC population compared with the HS-MEC-enriched population (Kendrick et al 2008).…”

Section: Ar Expression In Mammary Epitheliummentioning

confidence: 99%

“…This is expected given the luminalspecific identity of NOTCH3 lineage-traced cells in vivo . One exception to the luminalpromoting nature of NOTCH receptor engagement is NOTCH4, expression of which is more restricted to basal MECs (Harrison et al 2010b, Kannan et al 2013) and implicates a role in maintenance of basal stem/progenitor MECs in this sub-population. This was demonstrated using mammospheres to measure stem cell self-renewal of primary human MECs in vitro, where secondary sphere capacity was increased tenfold when cells were cultured in the presence of a NOTCH-activating synthetic peptide (Dontu et al 2004).…”

Section: Notch Function In Mammary Epitheliummentioning

confidence: 99%

Bringing androgens up a NOTCH in breast cancer

Tarulli

Butler

Tilley

et al. 2014

Endocrine-Related Cancer

View full text Add to dashboard Cite

While it has been known for decades that androgen hormones influence normal breast development and breast carcinogenesis, the underlying mechanisms have only been recently elucidated. To date, most studies have focused on androgen action in breast cancer cell lines, yet these studies represent artificial systems that often do not faithfully replicate/ recapitulate the cellular, molecular and hormonal environments of breast tumours in vivo. It is critical to have a better understanding of how androgens act in the normal mammary gland as well as in in vivo systems that maintain a relevant tumour microenvironment to gain insights into the role of androgens in the modulation of breast cancer development. This in turn will facilitate application of androgen-modulation therapy in breast cancer. This is particularly relevant as current clinical trials focus on inhibiting androgen action as breast cancer therapy but, depending on the steroid receptor profile of the tumour, certain individuals may be better served by selectively stimulating androgen action. Androgen receptor (AR) protein is primarily expressed by the hormone-sensing compartment of normal breast epithelium, commonly referred to as oestrogen receptor alpha (ERa (ESR1))-positive breast epithelial cells, which also express progesterone receptors (PRs) and prolactin receptors and exert powerful developmental influences on adjacent breast epithelial cells. Recent lineage-tracing studies, particularly those focussed on NOTCH signalling, and genetic analysis of cancer risk in the normal breast highlight how signalling via the hormone-sensing compartment can influence normal breast development and breast cancer susceptibility. This provides an impetus to focus on the relationship between androgens, AR and NOTCH signalling and the crosstalk between ERa and PR signalling in the hormone-sensing component of breast epithelium in order to unravel the mechanisms behind the ability of androgens to modulate breast cancer initiation and growth.

show abstract

“…Human luminal cells in the progenitor-enriched fraction are also distinct from basal cells in their possession of very short telomeres, sufficient to initiate a DNA damage response (Kannan et al., 2013, Kurabayashi et al., 2008). The cells in this subset also contain, and are resistant to, higher levels of reactive oxygen species, which results in their accumulation of detectable oxidative DNA damage (Kannan et al., 2014).…”

Section: Main Textmentioning

confidence: 99%

“…The cells in this subset also contain, and are resistant to, higher levels of reactive oxygen species, which results in their accumulation of detectable oxidative DNA damage (Kannan et al., 2014). Comprehensive epigenomic and deep global transcriptome data further underscore the biologic differences exhibited by these three phenotypes of normal human mammary cells: i.e., EpCAM + luminal cells with and without surface CD49f, and EpCAM − basal cells that are also CD49f + (Kannan et al., 2013, Lim et al., 2009, Pellacani et al., 2016, Raouf et al., 2008). …”

Section: Main Textmentioning

confidence: 99%

Basal-like Breast Cancers: From Pathology to Biology and Back Again

Gusterson

Eaves

2018

Stem Cell Reports

View full text Add to dashboard Cite

Human breast cancers referred to as “basal-like” are of interest because they lack effective therapies and their biology is poorly understood. The term basal-like derives from studies demonstrating tumor gene expression profiles that include some transcripts characteristic of the basal cells of the normal adult human mammary gland and others associated with a subset of normal luminal cells. Elucidating the mechanisms responsible for the profiles of basal-like tumors is an active area of investigation. More refined molecular analysis of patients' samples and genetic strategies to produce breast cancers de novo from defined populations of normal mouse mammary cells have served as complementary approaches to identify relevant pathway alterations. However, both also have limitations. Here, we review some of the underlying reasons, including the unifying concept that some normal luminal cells have both luminal and basal features, as well as some emerging new avenues of investigation.

show abstract

The Luminal Progenitor Compartment of the Normal Human Mammary Gland Constitutes a Unique Site of Telomere Dysfunction

Cited by 53 publications

References 42 publications

Glutathione-dependent and -independent oxidative stress-control mechanisms distinguish normal human mammary epithelial cell subsets

Glutathione-dependent and -independent oxidative stress-control mechanisms distinguish normal human mammary epithelial cell subsets

Bringing androgens up a NOTCH in breast cancer

Basal-like Breast Cancers: From Pathology to Biology and Back Again

Contact Info

Product

Resources

About