A single-gene biomarker identifies breast cancers associated with immature cell type and short duration of prior breastfeeding

Abstract

The pathogenesis of breast cancers that do not express estrogen receptors or Her-2/neu receptors (ERx/HER2x phenotype) is incompletely understood. We had observed markedly elevated gene expression of gamma-aminobutyric acid type A (GABA A ) receptor subunit p (GABAp, GABRP) in some breast cancers with ERx/HER2x phenotype. In this study, transcriptional profiles (TxPs) were obtained from 82 primary invasive breast cancers by oligonucleotide microarrays. Real-time reverse transcription-polymerase chain reaction (RT-PCR) was used to measure GABAp gene expression in a separate cohort of 121 invasive breast cancers. GABAp gene expression values from TxP and RT-PCR were standardized and compared with clinicopathologic characteristics in the 203 patients. GABAp gene expression was increased in 16% of breast cancers (13/82 TxP, 20/ 121 RT-PCR), particularly in breast cancers with ERx/HER2x phenotype (60%), and breast cancers with basal-like genomic profile (60%). The profile of genes coexpressed with GABAp in these tumors was consistent with an immature cell type. In multivariate linear regression analysis, the level of GABAp gene expression was associated with ERx/HER2x phenotype (P<0.0001), younger age at diagnosis (P = 0.0003), and shorter lifetime duration of breastfeeding (£ 6 months) in all women (P = 0.017) and specifically in parous women (P = 0.013). GABAp gene expression was also associated with combinations of high grade with ERx/HER2x phenotype (P = 0.002), and with Hispanic ethnicity (P = 0.036). GABAp gene expression is increased in breast cancers of immature (undifferentiated) cell type and is significantly associated with shorter lifetime history of breastfeeding and with high-grade breast cancer in Hispanic women.

Higher parity and shorter breastfeeding duration

“…However, these and other published data provide a strong clinical rationale for further scientific and epidemiologic research to directly evaluate any pathogenetic role for progenitor cells retained after cessation or weaning. 7,8 We observed a linear relationship between duration of breastfeeding per child and triple-negative BC phenotype (Fig. 2), without an obvious inflection point that would identify an optimal prevention target for breastfeeding duration.…”

“…8,17 This could theoretically be from repeated failure of an expanded progenitor cell population in breast tissue to naturally undergo differentiation and apoptosis from prolonged breastfeeding, producing a persistent pool of cells with survival capability and at potential risk for carcinogenesis and subsequent development of undifferentiated tumor phenotype (such as triple-negative BC). 8,[10][11][12][13][14][15] However, this hypothetical stochastic model might not predict the interval until cancer is detected, because of variable effects from each pregnancy and lactation, the timing and potency of subsequent carcinogenic events, and differing growth rates according to phenotype. We stress that we did not study progenitor cells or normal postpartum breast tissues from this patient cohort, and we did not directly study parity and breastfeeding as risk factors for future development of triple-negative BC.…”

“…[4][5][6][7] There is also a reported association with shorter lifetime duration of breastfeeding. [7][8][9] However, both parity and breastfeeding duration might contribute in combination to risk by altering the population of progenitor cells that are retained within breast parenchyma, a cell type that known to have enhanced survival potential under physiological or pathologic stress. 8,[10][11][12][13][14][15] Indeed, recruitment and expansion of progenitor cells within breast terminal ducts sustains epithelial expansion during pregnancy and lactation, and this is followed by epithelial differentiation or apoptosis during the course of weaning.…”

“…[7][8][9] However, both parity and breastfeeding duration might contribute in combination to risk by altering the population of progenitor cells that are retained within breast parenchyma, a cell type that known to have enhanced survival potential under physiological or pathologic stress. 8,[10][11][12][13][14][15] Indeed, recruitment and expansion of progenitor cells within breast terminal ducts sustains epithelial expansion during pregnancy and lactation, and this is followed by epithelial differentiation or apoptosis during the course of weaning. 16 However, it is not known what minimum duration of breastfeeding might induce differentiation of breast progenitor cells, or whether a combination of higher parity with repeated short or absent breastfeeding might augment the pathogenesis of BC with undifferentiated phenotype.…”

“…[22][23][24][25][26] Conversely, estrogen-independent phenotypes of BC might be associated with endocrine risk factors that are not related to lifetime estrogen exposure. 8,14,15 The study cohort was large, with an adequate proportion with triple-negative BC (19%), and we adjusted for recognized covariates and stratified by ethnicity. However, the lack of a cancer-free control group may limit our ability to generalize these results to the general population.…”