Unlocking the Mysteries of Lobular Breast Cancer Biology Needs the Right Combination of Preclinical Models

Abstract

Preclinical model systems are essential research tools that help us understand the biology of invasive lobular carcinoma of the breast (ILC). The number of well-established ILC models are increasing but remain limited. Lower incidence of ILC, under-representation of ILC patients in clinical trials, and intrinsic ILC tumor characteristics all contribute to this challenge. Hence, there is significant need to continually develop better model systems to recapitulate the essential characteristics of ILC biology, genetics, and histology, and empower preclinical therapeutic studies to be translated back into the clinic. In this Perspective, we highlight recent advances in in vivo experimental models, which recapitulate key features of ILC biology and disease progression and potentially reshape the future of ILC translational research. We assert that all existing in vitro and in vivo ILC preclinical models have their strengths and weaknesses, and that it is necessary to bridge key deficiencies in each model context as we move forward with ILC research. Thus, unlocking the mysteries of ILC will be best achieved by choosing the right combination of preclinical model systems.

Co-regulator activity of Mediator of DNA Damage Checkpoint 1 (MDC1) is associated with DNA repair dysfunction and PARP inhibitor sensitivity in lobular carcinoma of the breast

“…We noted that in ER+ ILC in TCGA, increased TMB as reported in cBio Portal was associated with high DDR score (as in Figure 5 It is important to consider that though TP53 mutations are uncommon in ILC, the cell line models used in our studies do carry TP53 mutations, which is typical of cancer cell lines including ILC (46)(47)(48). However, as noted above, MM134 and 44PE do mirror 'Proliferative' ILC regarding the elevated DNA damage response protein signature, and recent multi-omic profiling of putative ILC models supports that MM134 and 44PE are suitable models of ER+/luminal ILC (48).…”

Riluzole Suppresses Growth and Enhances Response to Endocrine Therapy in ER+ Breast Cancer

“…In all ILC models we tested except for the HCI-013EI PDX, riluzole plus fulvestrant provided greater growth inhibition than single-agent fulvestrant. Expansion of the PDE approach is an important strategy for rapidly diversifying the repertoire of preclinical ILC models [ 80 ] to test this and other novel endocrine therapy combinations, essential for a breast cancer subtype that has a significantly greater risk of late recurrence, and worse response to tamoxifen and the second-generation SERD AZD9496 [ 12 ]. Second, riluzole's multiple proposed or confirmed mechanisms of action—from inhibition of signaling through GRMs [ 24 ] and glutamate release via the glutamate/cystine antiporter SLC7A11 or X c − [ 81 ], to blockade of voltage-gated sodium channels [ 82 ], inhibition of internal ribosome entry site (IRES)-mediated protein synthesis [ 26 ], attenuation of RNA polymerase III complex assembly [ 83 ], and inhibition of Wnt/β-catenin signaling [ 84 ]—present a challenge to readily identifying patients who would benefit most from the drug.…”

Riluzole suppresses growth and enhances response to endocrine therapy in ER+ breast cancer

“…In all ILC models we tested except for the HCI-013EI PDX, Riluzole plus Fulvestrant provided greater growth inhibition than single-agent Fulvestrant. Expansion of the PDE approach is an important strategy for rapidly diversifying the repertoire of preclinical ILC models [77] to test this and other novel endocrine therapy combinations, essential for a breast cancer subtype that has a significantly greater risk of late recurrence, and worse response to Tamoxifen and the second-generation SERD AZD9496 [12]. Second, Riluzole’s multiple proposed or confirmed mechanisms of action - from inhibition of signaling through GRMs [24] and glutamate release via the glutamate/cystine antiporter SLC7A11 or X c - [78], to blockade of voltage-gated sodium channels [79], inhibition of internal ribosome entry site (IRES)-mediated protein synthesis [26], attenuation of RNA polymerase III complex assembly [80], and inhibition of Wnt/β-catenin signaling [81] – present a challenge to readily identifying patients who would benefit most from the drug.…”