Project Details


This study will investigate the molecular etiology that contributes to a special subset (30%-50%) of triple-negative breast cancers (TNBC) that are not associated with BRCA1 and p53. Our central hypotheses are: (1) 53BP1 loss confers a synthetic viability with BCCIP [BRCA2 and CDKN1A (p21) interacting protein] deficiency to promote breast cancer development by promoting the escape of dormancy and (2) 53BP1 loss modulates the sensitivity of the BRCAness cancer cells to molecular therapies targeted at homologous recombination (HR) defect.Preliminary Studies: BCCIP defects abrogate both HR and p53 simultaneously, and promote mammary tumorigenesis. BCCIP was originally identified as BRCA2 and p21 interacting protein. A unique feature of BCCIP is that it is not only involved in HR, but is also required for the activity of the wild-type p53. Therefore, BCCIP defects simultaneously abrogate the same HR functions carried out by BRCA1/BRCA2 and the activities of p53. In a recent study with >400 cases of breast cancers, we found that about one-third of all breast cancers are BCCIP negative. However, 49% of TNBC are BCCIP negative, while 25% of non-TNBC are BCCIP negative (p=6.6x10-07). In addition, BCCIP loss was found to be in a different subset of breast cancer tissues from the tumors with p53 or BRCA1 mutations. Using a conditional BCCIP knockdown mouse model, we found that >80% of the mice develop spontaneous mammary benign tumors with an average onset of 6.2 months, but the majority of these tumors remain in dormancy. However, about 10% of the dormant/benign tumors progressed into malignancy after a long latency (7-12 months). Interestingly, we found that 53BP1 expression was lost in all of the malignant tumors that evolved from the benign lesions. Coincidentally, we observed a striking correlation of negativities of 53BP1 and BCCIP in 30% of 128 triple-negative cancers (p=4x10-7).Rationale and Hypothesis: Considering (1) the conclusions from the above preliminary studies; (2) BCCIP is an essential gene that works in the same HR pathway of BRCA1; (3) 53BP1 deficiency is known to confer synthetic viability to BRCA1 deficient cells; (4) loss of 53BP1 has been shown to confer resistance to PARP inhibitors (PARPi), which contributes to tumor recurrence in HR-deficient cells; (5) BCCIP defects often impairs the cell growth that may contribute to the dormant status of the benign tumors; and (6) BCCIP downregulation is strongly associated with sensitivity to PARPi in ovarian cancer cells (it is yet to be determined in breast cancers), we hypothesize that 53BP1 loss synergizes with BCCIP deficiency to promote the mammary tumorigenesis. This may modulate the sensitivities of BCCIP-deficient tumors to PARPi and DNA cross-linking agents that target HR defects.Aim 1 will test the above hypothesis by building a new mouse model with concurrent BCCIP and 53BP1 deficiencies to determine the synergistic effect of 53BP1 and BCCIP deficiencies in the development of TNBC.Aim 2 will conduct functional characterization on the synthetic viability relationship between 53BP1 and BCCIP deficiency in cell growth and HR. This will help elucidate how 53BP1 loss helps BCCIP-deficient tumor cells escape growth dormancy.Aim 3 will determine the role of BCCIP deficiency in breast cancer sensitivity to therapies that specifically target HR defects, including PARPi and DNA cross-linking agents. We will also determine the role of 53BP1 loss in modulating these sensitivities.These studies may reveal the molecular etiology of 30%-50% of TNBC and offer foundations for informed treatment planning of one-third all breast cancers lacking of BCCIP expression.
Effective start/end date9/15/159/14/18


  • Congressionally Directed Medical Research Programs (CDMRP)


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